This grant is written in response to Program Announcement PA-03-171, Exploratory and Developmental Research Grants for Investigations in Rare Diseases. It is an R21 application proposing development of novel approaches to understand the molecular genetic basis for a rare cardiac disease, Arrhythmogenic Right Ventricular Dysplasia (ARVD). This is a heritable form of right ventricular cardiomyopathy characterized by a high incidence of life-threatening ventricular arrhythmias. The classic form of this disease has been shown to be caused by mutation in genes encoding elements of the cardiac desmosome, a subcellular structure that facilitates cellular adhesion. Using a large cohort of well phenotyped patients with this rare disease, the PI will characterize the molecular genetic basis for their disorder in a comprehensive manner. Within the 2 year period of this R21, the PI proposes 2 specific aims. First, using a cell-culture system well characterized for study of the desmosome, alterations in genes with mutations contributing to ARVD will be targeted for over- and under-expression in an effort to determine the relative contribution of haploinsufficiency versus dominant- negative interference in the pathogenesis of this disorder. Next, a novel approach for sequence analysis will be tested in a cohort of individuals with ARVD and compared to traditional sequencing. Additional candidate genes will be assessed for mutations contributing to ARVD in this cohort. The primary anticipated significance will be determination of the consequence of over- and under-expression of these genes in order to determine the feasibility of these approaches for therapy. The project utilizes novel techniques to modulate the level of desmosome mRNA in a cell culture system, and seeks to develop improved technology for sequence analysis of individuals with this disorder. The results of this R21 will provide the preliminary data to support future grant funding on the pathophysiology of this condition. Furthermore, improved understanding of the molecular genetic basis for this condition will help to identify genomic predictors of life-threatening ventricular arrhythmias among individuals with more common forms of cardiac disease, and will eventually lead to targeted therapies to modulate or prevent ARVD in genetically predisposed individuals. This application proposes investigation of the cause of an inherited heart disease called Arrhythmogenic Right Ventricular Dysplasia (ARVD). A more efficient type of genetic analysis will be tested. This will lead to better understanding of genetic susceptibility to sudden death from heart disease. [unreadable] [unreadable] [unreadable]